Distinct function of androgen receptor coactivator ARA70α and ARA70ß in mammary gland development, and in breast cancer.

ABSTRACT

Steroid receptor coactivators are important in regulating the function of the receptors in endocrine organ development and in cancers, including breast. Androgen receptor (AR) coactivator ARA70, was first identified as a gene fused to the ret oncogene and later characterized as an AR coactivator. We previously reported that the full length ARA70α functions as a tumor suppressor gene and that ARA70ß functions as an oncogene in prostate cancer. Here we show that both ARA70α and ARA70ß function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70α and ARA70ß serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70α transgenic mice and overgrowth of mammary glands in ARA70ß transgenic mice at virgin and pregnant stages. We determined that ARA70α inhibited cell proliferation, and that ARA70ß promotes proliferation in MCF7 breast cancer cells. These effects were observed in hormone-free media, or in media with androgen or estrogen, though to varying degrees. Additionally, we observed that ARA70ß strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70α expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70α and ARA70ß have distinct effects in mammary gland development and in the progression of breast cancer.